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cd8^+ T cell response mediates the therapeutic effects of oncolytic adenovirus in an immunocompetent mouse model

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Chinese Science Bulletin 2012年第1期57卷 48-53页

作者： YANG YaJun LI XiaoZhu WANG YaoHe WANG ShengDian Key Laboratory oflnfection and Immunity Institute of BiophysicsChinese Academy of SciencesBeijing 100101China Sino-British Research Center for Molecular Oncology Zhengzhou UniversityZhengzhou 450001China Center for Molecular Oncology Barts Cancer InstituteQueen Mary University of LondonLondon EC1M6BQUK

The role of anti-tumor immune responses in oncolytic adenoviral therapy has not been well studied due to lack of efficacious tu- mor model in immunocompetent ***,we evaluated the contributions of immune components to the therapeutic effects of oncolytic adenoviruse in an immunocompetent murine tumor model permissive for infection and replication of *** found that cd8+T cells were critical mediator for antitumor efficacy by oncolytic *** viral therapy induced intensive infiltration of cd8+T cells in tumor,increased tumor-specific IFN-?(interferon-?)production and CTL(cytotoxic T lymphocyte)activity of lymphocytes,and generated a long-term tumor-specific immune *** cd8+T cell responses by agonistic anti-4-1BB(cluster differentiation 137,cd137)antibody showed synergistic anticancer effects with oncolytic viro- *** results provide insight into antitumor mechanisms of oncolytic adenovirus in addition to their direct oncolytic effect.

关键词：腺病毒感染 T细胞反应治疗作用免疫反应小鼠模型 cd8 细胞毒性T淋巴细胞抗肿瘤机制

Proteomic analysis reveals distinctive protein profiles involved in cd8^(+) T cell-mediated murine autoimmune cholangitis

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Cellular & Molecular Immunology 2018年第8期15卷 756-767页

作者： Weici Zhang Ren Zhang Jun Zhang Ying Sun Patrick SC Leung Guo-Xiang Yang Zongwen Shuai William M Ridgway M Eric Gershwin Division of Rheumatology Allergy and Clinical ImmunologyUniversity of CaliforniaDavisCaliforniaUSA Department of Pathogenic Biology and Immunology Guangzhou University of Chinese MedicineGuangzhou 510006China Center for non-infectious liver diseases Beijing 302 HospitalBeijing 100039China Department of Rheumatology and Immunology The First Affiliated Hospital of Anhui Medical UniversityHefei 230022China Division of Immunology Allergy and RheumatologyUniversity of CincinnatiCincinnatiOH 45267

Autoimmune cholangitis arises from abnormal innate and adaptive immune responses in the liver,and T cells are critical drivers in this ***,little is known about the regulation of their functional behavior during disease *** previously reported that mice with T cell-restricted expression of a dominant negative form of transforming growth factor beta receptor type Ⅱ(dnTGFβ RII)spontaneously develop an autoimmune cholangitis that resembles human primary biliary cholangitis(PBC).Adoptive transfer of cd8^(+) but not cd4^(+) T cells into Rag1^(−/−)mice reproduced the disease,demonstrating a critical role for cd8^(+) T cells in PBC ***,we used SOMAscan technology to perform proteomic analysis of serum samples from dnTGFβRII and B6 control mice at different *** addition,we analyzed cd8 protein profiles after adoptive transfer of splenic cd8^(+) cells into Rag1^(−/−)*** use of the unique SOMAscan aptamer technology revealed critical and distinct profiles of cd8 cells,which are key to biliary *** total,254 proteins were significantly increased while 216 proteins were significantly decreased in recipient hepatic cd8^(+) cells compared to donor splenic cd8^(+) *** contrast to donor splenic cd8^(+) cells,recipient hepatic cd8^(+) cells expressed distinct profiles for proteins involved in chemokine signaling,focal adhesion,T cell receptor and natural killer cell-mediated cytotoxicity pathways.

关键词： autoimmune cholangitis cd8 dnTGFβRII mice proteomic analysis

PD-1^(+)cd8和PD-L1^(+)cd8肿瘤浸润性淋巴细胞联合评估对早期NSCLC复发的预测价值

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中华肿瘤防治杂志 2022年第8期29卷 564-570页

作者：张薇杨丽颖孙菊杰蔡思琪杨冠群邢力刚潍坊医学院临床学院山东潍坊261053 山东第一医科大学(山东省医学科学院)研究生部山东济南250117 山东省肿瘤防治研究院(山东省肿瘤医院)病理科山东第一医科大学(山东省医学科学院)山东济南250117 山东大学齐鲁医学院山东济南250012

目的分析早期非小细胞肺癌(NSCLC)患者PD-1^(+)cd8和PD-L1^(+)cd8肿瘤浸润淋巴细胞(TILs)的表达水平,并探讨对患者复发的影响.方法收集2014-01-01-2018-12-31在山东省肿瘤医院接受单纯根治性切除手术的170例早期原发性NSCLC患者的术后... 详细信息

目的分析早期非小细胞肺癌(NSCLC)患者PD-1^(+)cd8和PD-L1^(+)cd8肿瘤浸润淋巴细胞(TILs)的表达水平,并探讨对患者复发的影响.方法收集2014-01-01-2018-12-31在山东省肿瘤医院接受单纯根治性切除手术的170例早期原发性NSCLC患者的术后石蜡包埋组织标本,通过多重免疫荧光评估PD-1^(+)cd8和PD-L1^(+)cd8 TILs的密度.使用X-Tile取最佳截断值,将患者分为A组(PD-1^(+)cd8低+PD-L1^(+)cd8高)、B组(PD-1^(+)cd8高+PD-L1^(+)cd8高)、C组(PD-1^(+)cd8高+PD-L1^(+)cd8低)和D组(PD-1^(+)cd8低+PD-L1^(+)cd8低).比较各组的无复发生存时间(RFS).采用Cox比例风险回归模型分析影响患者预后的因素.结果170例早期NSCLC患者PD-1^(+)cd8与PD-L1^(+)cd8 TILs高浸润患者分别为70例(41.2%)和42例(24.7%).PD-L1^(+)cd8高的患者与复发有关联,χ^(2)=8.736,P=0.003.单因素分析结果显示,PD-L1^(+)cd8、PD-1^(+)cd8&PD-L1^(+)cd8水平与NSCLC患者预后有统计学意义关联,均Pcd8低(HR=0.39,95%CI:0.19~0.78,P=0.008)、PD-1^(+)cd8高+PD-L1^(+)cd8低(HR=0.13,95%CI:0.04~0.48,P=0.002)、PD-1^(+)cd8低+PD-L1^(+)cd8低(HR=0.27,95%CI:0.10~0.69,P=0.006)是早期NSCLC患者预后的独立影响因素.联合PD-1^(+)cd8与PD-L1^(+)cd8 TILs分析结果显示,A组的RFS较其他组短,C组的RFS较其他组长,4组间差异有统计学意义,χ^(2)=17.645,P=***8高组vs低组(χ^(2)=1.479,P=0.224)、PD-1^(+)cd8高组vs低组(χ^(2)=1.459,P=0.227)的RFS差异无统计学意义.PD-L1^(+)cd8高组的RFS低于PD-L1^(+)cd8低组,差异有统计学意义,χ^(2)=8.293,P=0.004.结论PD-1^(+)cd8和PD-L1^(+)cd8 TILs的联合评价对于研究肿瘤的免疫状态和指导NSCLC患者的术后治疗具有一定意义.

关键词：非小细胞肺癌 cd8 PD-1 PD-L1 肿瘤微环境

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中国病原生物学杂志 2022年第5期17卷 526-531页

作者：于明凯朱玥洁谢忻汝麦尔哈巴·艾斯卡尔张峰波尹紫月鲁晓擘丁剑冰新疆医科大学基础医学院新疆乌鲁木齐830011 新疆医科大学第一附属医院生殖助孕科新疆医科大学第一附属医院检验科新疆医科大学第一附属医院感染科

目的探索调节性T细胞(Treg)和cd8^(+)T细胞及其相关细胞因子在乙型肝炎病毒相关慢加急性肝衰竭(HBV-ACLF)患者中的表达变化及其临床意义。方法选取慢性乙型肝炎(CHB)患者47例,乙肝肝硬化(HBC)患者50例,慢性乙型肝炎相关ACLF(CHB-ACLF)患... 详细信息

目的探索调节性T细胞(Treg)和cd8^(+)T细胞及其相关细胞因子在乙型肝炎病毒相关慢加急性肝衰竭(HBV-ACLF)患者中的表达变化及其临床意义。方法选取慢性乙型肝炎(CHB)患者47例,乙肝肝硬化(HBC)患者50例,慢性乙型肝炎相关ACLF(CHB-ACLF)患者42例以及乙肝肝硬化相关ACLF(HBC-ACLF)患者45例,同时选取20例健康体检者作为健康对照(HC)。采用全自动生化分析仪测定研究对象的肝功指标,流式细胞术(FCM)检测Treg以及cd8^(+)T细胞比例,采用酶联免疫吸附测定法(ELISA)检测外周血中转化生长因子β(TGF-β)、白介素10(IL-10)、穿孔素(Perforin)和颗粒酶B(Granzyme B)的表达水平,采用Pearson法分析研究对象Treg和cd8^(+)T细胞以及相关细胞因子与肝功指标的相关性。结果CHB组患者Treg(8.84±0.77)%及相关细胞因子TGF-β(70.25±11.58)ng/mL和IL-10(6.03±1.40)pg/mL水平显著高于HC组(均Pcd8^(+)T细胞(32.64±5.26)%及其相关细胞因子Perforin(69.65±11.95)pg/mL和Granzyme B(37.51±3.71)pg/mL水平亦显著高于HC组(均P8±1.05)pg/mL水平显著低于CHB组(均Pcd8^(+)T细胞(36.94±4.94)%及其相关细胞因子Perforin(71.91±13.10)pg/mL和Granzyme B(97.53±8.93)pg/mL水平显著高于CHB组(均P8.15±1.13)%及相关细胞因子TGF-β(75.19±15.54)ng/mL和IL-10(5.85±0.74)pg/mL水平显著高于HC组(均Pcd8^(+)T细胞(33.60±4.00)%及其相关细胞因子Perforin(60.10±9.21)pg/mL和Granzyme B(41.61±5.06)pg/mL水平亦显著高于HC组(均P8)%及相关细胞因子TGF-β(46.84±7.80)ng/mL和IL-10(4.24±1.22)pg/mL水平显著低于HBC组(均Pcd8^(+)T细胞(42.57±4.68)%及其相关细胞因子Perforin(74.21±12.51)pg/mL和Granzyme B(88.89±9.61)pg/mL水平同样显著高于HBC组(均Pcd8^(+)T细胞及其细胞因子水平呈负相关,Treg及其细胞因子水平与肝功指标成负相关,而cd8^(+)T细胞及其细胞因子水平与肝功指标成正相关(均Pcd8^(+)T细胞及其细胞因子在HBV-ACLF患者中发生显著改变,Treg及其细胞因子水平与疾病严重程度成负相关,cd8^(+)T细胞及其细胞因子水平与疾病严重程度成正相关。HBV-ACLF发生时,Treg对cd8^(+)T细胞功能的抑制作用减弱,从而引起的机体促炎反应增强、抗炎反应减弱,可能是介导HBV-ACLF发病的重要因素。

关键词：慢加急性肝衰竭 ACLF Treg cd8 细胞因子

Therapeutic effect of curcumin on experimental colitis mediated by inhibiting cd8^+ cd11c^+ cells

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World Journal of Gastroenterology 2017年第10期23卷 1804-1815页

作者： Hai-Mei Zhao Fei Han Rong Xu Xiao-Ying Huang Shao-Min Cheng Min-Fang Huang Hai-Yang Yue Xin Wang Yong Zou Han-Lin Xu Duan-Yong Liu School of Basic Medical Sciences Jiangxi University of Traditional Chinese Medicine College of Pharmacy Jiangxi University of Traditional Chinese Medicine College of Pharmacy Hubei University of Traditional Chinese Medicine Department of Postgraduate Jiangxi University of Traditional Chinese Medicine Key Laboratory of Modern Preparation of TCM Ministry of EducationJiangxi University of Traditional Chinese Medicine Collaborative Innovation Center of TCM of New Products for Geriatrics Science and Technology College Jiangxi University of Traditional Chinese Medicine

AIM To verify whether curcumin (Cur) can treat inflammatory bowel disease by regulating cd8(+)cd11c(+) cells. METHODS We evaluated the suppressive effect of Cur on cd8(+)cd11c(+) cells in spleen and Peyer's patches (PPs) in colitis induced by trinitrobenzene sulfonic acid. Mice with colitis were treated by 200 mg/kg Cur for 7 d. On day 8, the therapeutic effect of Cur was evaluated by visual assessment and histological examination, while co-stimulatory molecules of cd8(+)cd11c(+) cells in the spleen and PPs were measured by flow cytometry. The levels of interleukin (IL)-10, interferon (IFN)-gamma and transforming growth factor (TGF)-beta 1 in spleen and colonic mucosa were determined by ELISA. RESULTS The disease activity index, colon weight, weight index of colon and histological score of experimental colitis were obviously decreased after Cur treatment, while the body weight and colon length recovered. After treatment with Cur, cd8(+)cd11c(+) cells were decreased in the spleen and PPs, and the expression of major histocompatibility complex., cd205, cd40, cd40L and intercellular adhesion molecule-1 was inhibited. IL-10, IFN-gamma and TGF-beta 1 levels were increased compared with those in mice with untreated colitis. CONCLUSION Cur can effectively treat experimental colitis, which is realized by inhibiting cd8(+)cd11c(+) cells.

关键词： cd8 cd11c Curcumin Experimental colitis Therapeutic effect

TGF-β1 Precursor and cd8 Are Potential Prognostic and Predictive Markers in Operated Breast Cancer

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Journal of Huazhong University of Science and Technology(Medical Sciences) 2014年第1期34卷 51-58页

作者：于海明杨俊兰焦顺昌王建东李莹 Department of Medical Oncology General Hospital of Chinese People’s Liberation Army Department of General Surgery General Hospital of Chinese People’s Liberation Army

The transforming growth factor β1（TGF-β1） and cd8-positive T cells are two important immune factors that function at opposite directions. The purpose of this study was to verify the relationship between the two factors and their associations with long-term effects of adjuvant chemotherapy or endocrine therapy in breast cancer. Expression of TGF-β1 precursor and cd8 was immunohistochemically detected on surgically-obtained tumor samples of 130（stageⅠ–Ⅲ） invasive breast carcinomas from Chinese subjects, who were followed up for a mean time of 112 months. Interstitial cd8-positive cells and TGF-β1 precursor-positive cells adjacent to tumor nests were counted. Infiltration of cd8-positive lymphocytes into tumor nests and TGF-β1 precursor expression in tumor cells were observed and survival analysis was performed. Our results showed that density of interstitial cd8-positive lymphocytes was an independent adverse prognostic factor for distant disease-free survival（DDFS）（HR=8.416, 95% CI=1.636–43.292, P=0.011） in hormone receptor-positive patients who were on adjuvant endocrine therapy. For breast cancer patients who did not receive adjuvant chemotherapy, those without infiltration of cd8-positive cells into tumor nests had a shorter overall survival（OS） than their counterparts with cd8-positive cell infiltration into tumor nests（Log-Rank, P=0.003）. But OS of patients without infiltration of cd8-positive cells into tumor nests was significantly prolonged by adjuvant chemotherapy（Log-Rank, P=0.013） and paralleled that of patients with cd8-positive cell infiltration. Although OS was shorter in the tumor cell TGF-β1 precursor（t-TGF-β1-pre）-positive patients than in the negative patients in patients without recieiving chemotherapy（P=0.053）, OS of t-TGF-β1-pre-positive patients was significantly prolonged by adjuvant chemotherapy（P=0.035） and was longer than that of t-TGF-β1-pre-negative patients. Analysis showed that t-TGF-β1-pre was an independent positive prognostic factor f

关键词： cd8 TGF-β1 breast cancer adjuvant endocrine therapy adjuvant chemotherapy dis-ease-free survival distant disease-free survival overall survival

活络效灵丹调控TCF1cd8干细胞样T细胞肿瘤浸润抑制小鼠三阴乳腺癌

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中国实验方剂学杂志 2024年

作者：罗波张曲孙玉洁刘林曾兰湖北省肿瘤医院放疗中心湖北省乳腺癌临床医学研究中心武汉市乳腺癌临床医学研究中心湖北省中医药大学中医学院湖北时珍实验室

目的：基于活络效灵丹对TCF1+cd8+干细胞样T细胞肿瘤浸润的调控作用探讨其抑制三阴乳腺癌小鼠肿瘤作用。方法：建立小鼠三阴乳腺癌移植瘤模型，随机分为模型组，活络效灵丹低、中、高剂量组(剂量3.9、7.8、15.6 g·kg-1)，程序性死亡受... 详细信息

目的：基于活络效灵丹对TCF1+cd8+干细胞样T细胞肿瘤浸润的调控作用探讨其抑制三阴乳腺癌小鼠肿瘤作用。方法：建立小鼠三阴乳腺癌移植瘤模型，随机分为模型组，活络效灵丹低、中、高剂量组(剂量3.9、7.8、15.6 g·kg-1)，程序性死亡受体-1（PD-1）组。各组按0.01 mL·g-1折算给药，模型组和PD-1组也给予等体积生理盐水，连续给药21d。PD-1组每周2次腹腔注射100 μg小鼠抗PD-1抗体，共5次注射。于不同时间测量小鼠瘤体积，以及小鼠的生存时间和肿瘤质量。苏木素-伊红（HE）染色观察肿瘤组织形态学改变；免疫组织化学及免疫荧光染色检测肿瘤组织中cd8+T细胞及TCF1+cd8+干细胞样T细胞表达的差异；流式细胞术检测肿瘤中免疫细胞亚群的差异，检测肿瘤及外周血中TCF1+cd8+干细胞样T细胞表达的差异。蛋白免疫印迹法检测肿瘤组织中PD-L1的蛋白表达水平。结果：与模型组比较，活络效灵丹低、中、高剂量组及PD-1组肿瘤体积及质量均降低（P＜0.05，P＜0.01）；活络效灵丹低、中、高剂量组和PD-1组小鼠中位生存时间为27.00 d （95%CI，0.45-2.65），31.00 d （95%CI，0.32-1.89），34.00 d （95%CI，0.40-2.33），35.00 d （95%CI，0.42-2.47），均高于模型组24.50 d （95%CI， 0.37-10.5）。流式细胞术显示：与模型组比较，活络效灵丹低、中、高剂量组及PD-1组肿瘤中浸润cd8+T细胞占比和数量均升高，差异有统计学意义（P＜0.05，P＜0.01），肿瘤调节性T细胞（Treg）和M2型巨噬细胞占比减小（P＜0.05）。与模型组比较，活络效灵丹低、中、高剂量组及PD-1组肿瘤中IFN-γ+cd8+T和GrzB+cd8+T细胞占比均升高（Pcd8+T细胞在cd8+T细胞中的占比均升高，免疫荧光染色进一步显示活络效灵丹低、中、高剂量组TCF1+cd8+T细胞在肿瘤组织数目增多。免疫印迹分析显示与模型组比较，活络效灵丹低、中、高剂量组肿瘤组织中PD-L1蛋白表达未见明显降低。结论：活络效灵丹通过增加TCF1+cd8+干细胞样T细胞肿瘤浸润及cd8+T细胞活性，并调节M2巨噬细胞和调节性T细胞免疫细胞亚群增强抗肿瘤免疫，从而发挥抑制模型小鼠三阴乳腺癌的作用。该研究为活络效灵丹临床应用于乳腺癌和联合免疫治疗提供更多的理论依据。

关键词：活络效灵丹乳腺癌三阴乳腺癌 cd8 T淋巴细胞抗肿瘤免疫干细胞

结直肠癌中IL-38与cd4、cd8的相关性及临床意义

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临床与实验病理学杂志 2023年第5期39卷 531-536页

作者：袁柳红陈飞儿谈振宇张凤赵一鸣包士三陶琨上海交通大学医学院附属同仁医院病理科上海200050

目的探讨IL-38在结直肠癌(colorectal cancer,CRC)组织中的表达与cd4、cd8表达的相关性及与预后的关系。方法收集314例CRC临床资料,采用免疫组化SP法检测IL-38、cd4、cd8、IL-6、IL-10、IL-23和TGF-β的表达,分析其临床病理特征并复习... 详细信息

目的探讨IL-38在结直肠癌(colorectal cancer,CRC)组织中的表达与cd4、cd8表达的相关性及与预后的关系。方法收集314例CRC临床资料,采用免疫组化SP法检测IL-38、cd4、cd8、IL-6、IL-10、IL-23和TGF-β的表达,分析其临床病理特征并复习相关文献。结果IL-38在癌组织(H score:166.7)中的表达水平明显低于癌旁组织(H score:194.4)(P8与cd8表达呈正相关(r=0.1154,P=0.0392),IL-38与cd4表达无明显相关性(r=0.0249,P=0.6499)。IL-38与IL-10(r=-0.1129,P=0.0394)、IL-23(r=-0.1126,P=0.0362)、TGF-β(r=-0.1618,P=0.003)表达呈负相关。IL-38和cd8双高表达的患者3年生存率,明显高于IL-38和cd8单高表达或双低表达的患者(P=0.0363)。Cox多因素生存分析:IL-38与cd8双高表达是CRC患者预后良好的独立影响因素(HR=0.175,95%CI:0.037~0.826,P=0.028)。结论IL-38和cd8+T细胞可能通过调节肿瘤微环境影响CRC的进展,联合评估IL-38与cd8的表达是CRC患者术后的独立预测因素。

关键词：结直肠肿瘤 IL-38 cd4 cd8 预后生存分析

冠心病患者cd8、PD-1、PD-L1、TGF-β_(1)、MMP-14血浆含量与冠状动脉狭窄程度的相关性分析及预测价值

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华中科技大学学报（医学版） 2022年第1期51卷 88-94页

作者：郭娜赵凯金珊王成燕沈西华蔡文平段军仓刘克坚庞丽娟石河子大学医学院第一附属医院病理科/国家卫生健康委中亚高发病防治重点实验室/石河子大学医学院病理学系/新疆地方与民族高发病教育部重点实验室石河子832002 浙江省金华市中心医院心内科金华321000 石河子大学医学院第一附属医院心内科石河子832002

目的借助生物信息学分析和临床样本检测,探究人血浆白细胞分化抗原(cd8)、程序性死亡受体-1(programmed cell death protein-1,PD-1)、细胞程序性死亡配体-1(programmed cell death ligand-1,PD-L1)、转化生长因子-β_(1)(transforming growth factor-β_(1),TGF-β_(1))和膜型基质金属蛋白酶-1(membrane type 1 matrix metalloproteinase, MT1-MMP,又名MMP-14)与冠心病发病过程及冠状动脉狭窄程度的相关性,为冠心病的早期筛查及预测提供新的思路。方法通过生物信息学分析,对cd8、PD-1、PD-L1、TGF-β_(1)、MMP-14进行GO和KEGG通路富集分析,并构建各分子间PPI网络图。选取39例冠心病患者作为研究对象,根据Gensini评分系统将其冠状动脉狭窄程度分为轻、中、重3组,采用酶联免疫吸附法(ELISA)检测各组cd8、PD-1、PD-L1、TGF-β_(1)、MMP-14血浆含量,并分析各分子血浆含量与患者Gensini评分的相关性,评估其对冠心病发病的预测价值。结果 GO和KEGG通路富集分析显示cd8、PD-1、PD-L1、TGF-β_(1)、MMP-14可作用于冠心病及其炎症反应通路,PPI网络分析显示各分子间具有一定相互作用关系。PD-L1血浆含量与Gensini评分呈显著正相关。cd8、PD-1、TGF-β_(1)、MMP-14与Gensini评分线性关系不显著,但是从趋势上看PD-1及MMP-14血浆含量与Gensini评分存在正相关趋势,cd8及TGF-β_(1)与Gensini评分存在负相关趋势。结论 cd8、PD-1、PD-L1、TGF-β_(1)、MMP-14可联合作用于冠心病的发生发展过程,各分子血浆含量与冠状动脉狭窄程度存在一定程度相关,可能作为冠状动脉狭窄程度的预测指标。

关键词： cd8 PD-1/PD-L1 TGF-β_(1) MMP-14 冠心病